1. Field of the Invention
The present invention generally relates to compounds, compositions, and methods for treating pancreatitis. Specifically, the present invention relates to compounds, compositions, and methods for inhibiting the key molecular pathways that mediate pancreatitis, which compounds and compositions include curcumin compounds and inhibitors of reactive oxygen species (ROS).
2. Description of the Related Art
Pancreatitis is generally divided into acute pancreatitis and chronic pancreatitis. See Topazian M, et al. (1999) “Acute Pancreatitis” TEXTBOOK OF GASTROENTEROLOGY Philadelphia: Lippincott Willimas & Wilkins, p. 2121–2150; Owyang C. (1999) “Chronic Pancreatitis” TEXTBOOK OF GASTROENTEROLOGY Philadelphia: Lippincott Willimas & Wilkins, p. 2151–2177. Acute pancreatitis is characterized by acute inflammation in the pancreas accompanied by necrosis of the parenchymal cells, i.e. acinar cells, and duct cells. The most common causes of acute pancreatitis are alcoholism and gallstone disease. Alcohol sensitizes the pancreas to the inflammatory response and inhibition of this inflammatory response results in improvement in the severity of the pancreatitis. See Pandol SJ, et al. (1999) Gastroenterology 117:706–716. Gallstones cause pancreatitis by both obstructing the pancreatic duct and causing reflux of bile into the pancreatic duct as the stones migrate from the gallbladder to the common bile duct, ampulla of Vater and duodenum. See Topazian M, et al. (1999). Bile reflux-induced pancreatitis can also be ameliorated by inhibition of the inflammatory response. See Vaquero E, et al. (2001) Am J Physiol 280:G1197–G1208. Chronic pancreatitis results from continued episodes of acute pancreatitis and is most commonly caused by ethanol abuse. See Owyang C. (1999). Development of chronic pancreatitis includes chronic inflammation as well fibrosis and loss of parenchymal tissue. See Vaquero E, et al. (1999) Gut 45:269–277.
A substantial body of evidence indicates that one of the first events in the development of pancreatitis is the initiation of an inflammatory response in the parenchymal cells of the pancreas. The pancreatic acinar cell is capable of responding to noxious stimuli by upregulating signaling systems that regulate the production of pro-inflammatory inflammatory cytokines/chemokines and other inflammatory molecules. See Pandol S J, et al. (1999) Gastroenterology 117:706–716; Vaquero E, et al. (2001); Vaquero E, et al. (1999); Bhatia M, et al. (2000) J Pathol 190:117–125; Norman J (1998) Am J Surg 175:76–83; Schmid R M, et al. (1999) Eur J Gastroenterol Hepatol 11:125–127; Gukovsky I, et al. (1998) Am J Physiol 275:G1402–G1414; Blinman T A, et al. (2000) Am J Physiol 279:C1993–C2003; Frossard J L, et al. (1999) Gastroenterology 116:694–701; Gukovskaya A S, et al. (1997) J Clin Invest 100:1853–1862; Han B, et al. (1999) Am J Physiol 277:C74–C82; and Zaninovic V, et al. (2000) Am J Physiol 279:G666–G676. The signaling systems include the activation of the transcription factors, nuclear factor-κB (NF-κB) and activating peptide-1 (AP-1), as well as p38 MAP kinase. See Blinman T A, et al. (2000). The proinflammatory cytokines/chemokines include tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), IL-8, monocycte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and the like. Other inflammatory molecules upregulated by these signaling systems include inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1). See Zaninovic V, et al. (2000).
Inhibition of the inflammatory signaling systems by N-acetylcysteine, an antioxidant, results in the attenuation of both the inflammatory response and parenchymal injury responses of pancreatitis. See Vaquero E, et al. (2001); and Gukovsky I, et al. (1998). That is, the inhibition results in decreased expression of cytokines/chemokines and inflammatory cell infiltration in the pancreas. In addition, the inhibition of the inflammatory response results in significant reduction in the parenchymal injury, such as necrosis of parenchymal cells and activation of digestive enzymes. See Vaquero E, et al. (2001); Gukovsky I, et al. (1998); Gukovskaya A S, et al. (1997); Zaninovic V, et al. (2000); and Sandoval D, et al. (1996) Gastroenterology 111:1081–1091. Thus, the inflammatory response represents a central event in the mechanism of pancreatitis.
Currently, there are no therapies for either acute of chronic pancreatitis that address the mechanism of the disease. See Topazian M, et al. (1999). Prior art therapies are merely supportive measures that keep patients alive during an episode of acute pancreatitis, and measures to deal with complications of the disease during both the acute and chronic stages. As a result of a lack of therapeutic strategies directed to the mechanism of pancreatitis, prior art therapies have had little effect in decreasing the morbidity and mortality due to pancreatitis.
Thus, a need still exists for compounds, compositions, and methods for treating, preventing, and inhibiting pancreatitis.